Important studies challenging previous approaches to the treatment of adults with Philadelphia chromosome-negative acute lymphoblastic leukemia (ALL) have emerged in the past decade. Donor versus no donor comparisons of allogeneic transplant highlight a potent graft-versus-leukemia effect in ALL, and the application of reduced-intensity conditioning transplants may exploit this effect while reducing non-relapse mortality. The adoption of the use of pediatric intensity-type regimens in adolescents and young adults shows promise to improve outcomes in this population. New therapeutic targets such as mutations in NOTCH1 in T-cell ALL and CD22 in pre-B ALL are being exploited in clinical trials. The application of molecular techniques and flow cytometry to quantitate minimal residual disease will allow further stratification of patients by risk. Although the outcomes of adults with ALL lag behind the stunningly successful results seen in children, new paradigms and new discoveries bring hope that this disparity will steadily lessen.